The overlapped highways run east along the north bank of the Clearwater River for 7.3 miles (11.7 km), leaving Lewiston and entering the Nez Perce Indian Reservation before separating.

[1] US-12 then continues east along the north bank of the Clearwater River through northern Lapwai, past the Ant and Yellowjacket rock formation and a historical marker for the Spalding Mission.

[1][5] In Lewis County, US-12 continues southeast along the south bank of the Clearwater River, intersecting SH-11 at Greer and passing a historical marker for a ferry operated in the original 1860 goldrush.

It then enters Idaho County and continues south along the north bank of the Clearwater River, crossing the Nez Perce National Historical Park.

In the park, it passes a historical marker for two sites located about two miles (3.2 km) away, commemorating the Lewis and Clark Long Camp of 1806 and the Asa Smith mission of 1839 to 1841.

The highway then turns east along the north bank of the Clearwater River, passing a historical marker commemorating the camp of Nez Perce led by Looking Glass, and the 1877 attack by the U.S. Army on July 1 that provoked Looking Glass to join the Nez Perce retreat with Chief Joseph.

US-12 through Idaho has been proposed as a route for shipment of huge equipment from Lewiston, an inland port,[32] to oil sands facilities near Fort McMurray, Alberta and to a refinery in Billings, Montana.

A permit granted by the Idaho Transportation Department to ConocoPhillips in August 2010 is the subject of litigation initiated by householders along the route.

[34] On January 19, 2011, it was announced that the Idaho government would issue permits for four loads of refinery equipment to be transported from Lewiston to Billings.